Piperacillin Tazobactam,

Ceftriaxone Tazobactam &

Cefoperazone Sulbactam
Dr Keshab Raj Neupane
FCPS Resident
 Mechanism of Action:
• these three substances resemble β-lactam
molecules & are potent
inhibitors of “most” plasmid-mediated beta-
lactamases.
• Sulbactam has intrinsic activity against
Acinetobacter & may be used against MDR
strains.
 Piperacillin-Tazobactam
(Durataz, Piptaz, Pipzo, Maxotaz)
• Piperacillin is a broad-spectrum β-lactam
antibiotic of the ureidopenicillin class.
• The chemical structure of piperacillin and other
ureidopenicillins incorporates a polar side chain
that enhances penetration into gram-negative
bacteria and reduces susceptibility to cleavage by
gram-negative beta lactamase enzymes.
• These properties confer activity against the
important hospital pathogen Pseudomonas
aeruginosa. Thus piperacillin is sometimes
referred to as an "anti-pseudomonal penicillin”.
 Pharmacology
• Excretion: ~70% excreted unchanged in the
urine.
• Protein binding: ~30%
• Penetration is excellent, including some entry
into inflamed meninges. Extremely high levels
in bile make this a good choice for biliary tract
infections.
• Mechanism: inhibits synthesis of bacterial cell
wall
 Dosage:
• Usual dosage range: I.V.: 3.375 g every 6 hours
or 4.5 g every 6-8 hours; maximum: 18 g/day
• Extended infusion method (unlabeled dosing):
3.375-4.5 g I.V. over 4 hours every 8 hours
(Kim, 2007; Shea, 2009); an alternative
regimen of 4.5 g I.V. over 3 hours every 6
hours has also been described (Kim, 2007)
 Coverage
• Gram-positive coverage:
Covers: MSSA, non-enterococcal streptococci, vancomycin-sensitive
enterococci
Misses: MRSA, vancomycin-resistant enterococci, coagulase-negative
staph
• Gram-negative coverage: Excellent (covers most pseudomonas)
Warning: Be careful with bacteria that are resistant to ceftriaxone and
sensitive to piperacillin-tazobactam (especially E. coli & Klebsiella
pneumoniae); this sensitivity pattern suggests extended-spectrum
beta-lactamase resistant bacteria, which may be better treated with a
carbapenem
• Anaerobic coverage: Excellent (misses Clostridioides difficile)
 Adverse Effects
• Gastrointestinal: Diarrhea
• Central nervous system: Insomnia , headache ,
fever , agitation
• Dermatologic: Rash , pruritus.
• Hematologic: Leukopenia, thrombocytopenia
• Associated with lower rate of Clostridioides
difficile than broad-spectrum cephalosporins
(e.g. cefepime).
 Indication
• Treatment of moderate-to-severe infections caused by
susceptible organisms, including
– infections of the lower respiratory tract (community-acquired
pneumonia, nosocomial pneumonia);
– uncomplicated and complicated skin and skin structures
(including diabetic foot infections);
– gynecologic (endometritis, pelvic inflammatory disease); and
– intra-abdominal infections (appendicitis with rupture/abscess,
peritonitis).
• Tazobactam expands activity of piperacillin to include beta-
lactamase producing strains of S. aureus, H. influenzae, E.
coli, Bacteroides spp, and other gram-positive and gram-
negative aerobic and anaerobic bacteria.
 Renal Dosing
• Traditional infusion method (ie, I.V. infusion over
30 minutes): Manufacturer’s labeling:
• -Clcr >40 mL/minute: No dosage adjustment
required.
• -Clcr 20-40 mL/minute: Administer 2.25 g every 6
hours (3.375 g every 6 hours for nosocomial
pneumonia)
• -Clcr <20 mL/minute: Administer 2.25 g every 8
hours (2.25 g every 6 hours for nosocomial
pneumonia)
Points to be Noted:
Ceftriaxone-Tazobactam
(1000mg + 125mg)
 Mechanism of action
• Ceftriaxone interferes with the biosynthesis of
the peptidoglycan component of the bacterial
cell way by binding to and inactivating
penicllin-binding proteins (PBPs).
• Tazobactam is a penicillanic acid sulfone
derivative with β-lactamase inhibitory
properties. It enhances the activity of β-
lactam antibacterials against β-lactamase-
producing bacteria.
 Pharmacology
• Peak plasma time: 2-3 hrs
• Distribution: distributed throughout body
including Gall bladder, lungs, bone, bile and
CSF, crosses placenta
• Protein bound: 85-95%
• Metabolism: hepatic
• Elimination: half life : 5-9 hr
• Excretion: urine , feces
• IV/IM administration
• Dilute with NS, D5W (incompatible with RL)
• IV infuse over 30 minutes
• IM inject into large muscle mass
Coverage
 Adverse Effects
• Superinfection; anaphylaxis; diarrhoea; local reactions;
blood dyscrasias; rash, fever, pruritus; elevated
transaminases and alkaline phosphatase. GI effects;
pseudomembranous colitis; hematologic effects;
hypersensitivity reactions; CNS disturbances; hypertension;
chest pain; edema; moniliasis; rhinitis; dyspnea;
hypotension; ileus; syncope; local Inj site reactions; rigors.

• Potentially Fatal: Pseudomembranous colitis;

nephrotoxicity.
• Disulfiram-like reaction with alcohol.
• Nephrotoxicity with aminoglycosides and furosemide.
 Indications:
• Acute bacterial otitis media:
– Caused by Streptococcus pneumoniae, Haemophilus influenzae
(including beta-lactamase-producing strains), or Moraxella
catarrhalis (including beta-lactamase-producing strains).
• Bacterial septicemia:
– Caused by Staphylococcus aureus, S. pneumoniae, Escherichia
coli, H. influenzae, or Klebsiella pneumoniae.
• Bone and joint infections:
– Caused by S. aureus, S. pneumoniae, E. coli, Proteus mirabilis, K.
pneumoniae, or Enterobacter spp.
• Intra-abdominal infections:
– Caused by E. coli, K. pneumoniae, Bacteroides fragilis,
Clostridium spp., or Peptostreptococcus spp.
• Lower respiratory tract infections:
– Caused by S. pneumoniae, S. aureus, H. influenzae,
Haemophilus parainfluenzae, K. pneumoniae, E. coli,
Enterobacter aerogenes, P. mirabilis, or Serratia
marcescens.
• Meningitis:
– Caused by H. influenzae, Neisseria meningitidis, or S.
pneumoniae. Ceftriaxone has also been used successfully
in a limited number of cases of meningitis and shunt
infection caused by Staphylococcus epidermidis and E. coli
(efficacy for these 2 organisms in this organ system was
studied in fewer than 10 infections).
• Pelvic inflammatory disease:
– Caused by N. gonorrhoeae.
• Skin and skin structure infections:
– Caused by S. aureus, S. epidermidis, Streptococcus
pyogenes, viridans group streptococci, E. coli,
Enterobacter cloacae, Klebsiella oxytoca, K.
pneumoniae, P. mirabilis, Morganella morganii,
Pseudomonas aeruginosa, S. marcescens,
Acinetobacter calcoaceticus, or B. fragilis, or
Peptostreptococcus spp.
• Surgical prophylaxis:
– surgical procedures classified as contaminated or potentially
contaminated (eg, vaginal or abdominal hysterectomy or
cholecystectomy for chronic calculous cholecystitis in high-risk
patients, such as those older than 70 years, with acute
cholecystitis not requiring therapeutic antimicrobials,
obstructive jaundice, or common duct bile stones) and
– in surgical patients for whom infection at the operative site
would present serious risk (eg, during coronary artery bypass
surgery).
• Uncomplicated gonorrhea (cervical/urethral and rectal):
– Caused by N. gonorrhoeae, including both penicillinase- and
nonpenicillinase-producing strains, and pharyngeal gonorrhea
caused by nonpenicillinase-producing strains of N. gonorrhoeae.
• Urinary tract infections (complicated and uncomplicated):
– Caused by E. coli, P. mirabilis, Proteus vulgaris, M. morganii, or
K. pneumoniae.
• Expressed in terms of ceftriazone/tazobactam:
1000/125 mg once daily or in equally divided
doses twice a day. Total daily dose should not
exceed 4 g of ceftriaxone.
• Continue treatment for at least 2 days after the
signs and symptoms have resolved.
• Usual duration: 7-14 days; longer treatment may
be needed in more serious infections.
• For Streptococci pyogenes infections, treatment
should continue for at least 10 days.
 Renal Dosing
• Renal adjustment not needed.
 Points to be Noted:
• Risk of fatal calcium-ceftriaxone precipitant
formation in lungs and kidneys of term and
preterm neonates (
• Calcium may be given in sequence once
infusion line has been flushed (chemically
incompatible)
 Contraindications:
• Allergic reactions
• C. difficile bacterial infection
• Pseudomembranous colitis
• Hyperbilirunemic infants
• Hypersensitivity with cephalosporins
Cefoperazone-Sulbactam

1000+500/ 2000+1000
• Cefoperazone is a 3rd generation
cephalosporin with activity against
Pseudomonas aeroginosa.
• Cefoperazone-Sulbactam combination makes
antibiotic more effective because Sulbactam
prevents degeneration of Cefoperazone.
 Coverage
• Sulperazon - "protected" (Cefoperazone +
Sulbactam)
• Spectrum: wide G+, Gr-, anaerobes
• Resistant to β-lactamases of extended spectrum
(sulperazon and carbapenems)
• Application: for severe community-acquired and
hospital-acquired infective processes: primary
and secondary peritonitis, infected pancreatic
necrosis, sepsis, diabetic foot, phlegmons,
nosocomial pneumonia.
 Indication
• Upper and lower respiratory and urinary tract
infections;
• skin, soft tissue, bone and joint infections;
• septicemia, meningitis,
• peritonitis, cholecystitis, cholangitis,
• pelvic inflammatory disease, endometritis,
gonorrhea, and
• other abdominal and genital tract infections
 Adverse Effects
• Hypersensitivity
– contact dermatitis
– Hypersensitivity reactions, often manifested as skin
rashes, are common with cefoperazone and may
require drug discontinuation.
– Drug fever and changes in Coombs' tests have also
been reported.
– Allergic cross-reactivity may occur in patients allergic
to penicillin.
– Cephalosporin class antibiotics have been associated
with anaphylaxis, Stevens-Johnson syndrome,
erythema multiforme, and toxic epidermal necrolysis
Gastrointestinal
• diarrhea (due to the disturbance of intestinal flora from high biliary
concentrations of cefoperazone).
• Gastrointestinal side effects have included nausea, vomiting and diarrhea,
the latter being the most frequent.
• Clostridium difficile has been documented in some patients receiving
cefoperazone

Hepatic
• alterations in serum transaminases and alkaline phosphatase in 5% to 10%
of patients,
• usually mild and transient and return to normal following completion of
therapy.
• Cephalosporins as a class have been associated with hepatic dysfunction
including cholestasis
• Hematologic
– prolongation of prothrombin time and partial
thromboplastin time
– Bleeding occurred in some cases.
– eosinophilia, neutropenia, decreases in hemoglobin
and hematocrit, thrombocytopenia,
hypoprothrombinemia, and leukopenia.
– Cephalosporins as a class have been associated with
aplastic anemia, hemolytic anemia, prolonged
prothrombin time, hemorrhage, neutropenia,
pancytopenia, and agranulocytosis.
• Renal
– transient elevations of BUN and creatinine, and acute
interstitial nephritis with renal failure.
– Cephalosporins as a class have been associated with
renal dysfunction and toxic nephropathy.
• Local
– pain after intramuscular injection and phlebitis
• Dermatologic
– rash, Stevens-Johnson syndrome, erythema
multiforme, and toxic epidermal necrolysis.
• Nervous system
– seizures in renally impaired patients
 Dosing
• Renal Dose Adjustments
– No adjustment recommended
• Liver Dose Adjustments
– If doses greater than 4 g/24 hours are required in patients
with liver disease, monitor serum levels closely.
– In patients with both liver dysfunction and significant renal
impairment, doses should not exceed 1 to 2 g/day without
close monitoring of serum levels.
• Dose Adjustments
– In patients with both hepatic dysfunction and significant
renal disease, dosage should not exceed 1 to 2 g/day
without close monitoring of serum levels.
 Points to be Noted:
• If C trachomatis is a suspected pathogen,
appropriate antichlamydial coverage should
be added, because cefoperazone has no
activity against this organism.

• Patients should avoid alcoholic beverages for

at least 72 hours after cefoperazone
administration.
 References:
• Uptodate
• Drugs.com